This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-1976v1 69/9/3779    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pampalakis, G. Articles by Sotiropoulou, G. Search for Related Content PubMed PubMed Citation Articles by Pampalakis, G. Articles by Sotiropoulou, G.

A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition

¹ Department of Pharmacy, University of Patras, Rion-Patras, Greece; ² Biomedical Sciences Research Center "Alexander Fleming", Vari, Attiki, Greece; ³ Foundation of Biomedical Research of the Academy of Athens, and ⁴ National Hellenic Research Foundation, Athens, Greece

Requests for reprints: Georgia Sotiropoulou, Department of Pharmacy, University of Patras, Rion-Patras 26500, Greece. Phone: 30-2610-969939; Fax: 30-2610-969940; E-mail: gdsotiro{at}upatras.gr.

Key Words: Human kallikrein-related peptidase 6/protease M/zyme/neurosin • epigenetic silencing • tumor suppressor • epithelial-to-mesenchymal transition • breast cancer

Human kallikrein-related peptidase 6 (KLK6) was cloned as a putative class II tumor suppressor based on its inactivated expression in metastatic breast cancer. Here, we investigated the mechanism(s) underlying the silencing of KLK6 gene in metastatic breast cancer and its putative implications for tumor progression. We present evidence that tumor-specific loss of KLK6 expression is due to hypermethylation of specific CpGs located in the KLK6 proximal promoter. Methylation-dependent binding of methyl CpG-binding protein 2 and the formation of repressive chromatin mediated by localized histone deacetylation are critical components of KLK6 silencing in breast tumors. Re-expression of KLK6 in nonexpressing MDA-MB-231 breast tumor cells by stable cDNA transfection resulted in marked reversal of their malignant phenotype, manifested by lower proliferation rates and saturation density, marked inhibition of anchorage-independent growth, reduced cell motility, and their dramatically reduced ability to form tumors when implanted in severe combined immunodeficiency mice. Interestingly, inhibition of tumor growth was observed at physiologic concentrations of KLK6, but not when KLK6 was highly overexpressed, as observed in a subset of breast tumors. Differential proteomic profiling revealed that KLK6 re-expression results in significant down-regulation of vimentin which represents an established marker of epithelial-to-mesenchymal transition of tumor cells and in concomitant up-regulation of calreticulin and epithelial markers cytokeratin 8 and 19, indicating that KLK6 may play a protective role against tumor progression that is likely mediated by inhibition of epithelial-to-mesenchymal transition. We suggest that KLK6 is an epigenetically regulated tumor suppressor in human breast cancer and provide ways of pharmacologic modulation. [Cancer Res 2009;69(9):3779–87]

This article has been cited by other articles:

				G. Sotiropoulou, G. Pampalakis, and E. P. Diamandis Functional Roles of Human Kallikrein-related Peptidases J. Biol. Chem., November 27, 2009; 284(48): 32989 - 32994. [Abstract] [Full Text] [PDF]